N-alkylsulfonyl benzoylhaloalkylsulfonanilides

ABSTRACT

N-ALKYLSULFONYL BENZOYLHALOALKYLSULFONALIDES IN WHICH THE AROMATIC RINGS ARE OPTIONALLY SUBSTITUTED. THESE COMPOUNDS ARE ACTIVE ANTI-INFLAMMATORY AGENTS.

United States Patent Oflice Patented May 9, 1972 3,661,990N-ALKYLSULFONYL BENZOYLHALOALKYL- SULFONANILIDES Joseph KennethHarrington, Edina, Minn., assignor to Riker Laboratories, Inc.,Northridge, Calif.

N Drawing. Filed Apr. 13, 1970, Ser. No. 28,123 Int. Cl. C07c 143/74 US.Cl. 260-556 F 11 Claims ABSTRACT OF THE DISCLOSURE N-alkylsulfonylbenzoylhaloalkylsulfonalides in which the aromtaic rings are optionallysubstituted. These compounds are active anti-inflammatory agents.

This invention relates to N-alkylsulfonyl benzoylhaloalkylsulfonanilidesin which the aromatic rings are optionally substituted. These compoundsare active anti-inflammatory agents and some also are analgesic,antipyretic and anti-microbial agents.

It is an object of the invention to provide compounds which areanti-inflammatory agents.

It is another object of the invention to provide compounds for thecontrol of microbes.

It is another object of the invention to provide compounds which areanalgesic agents.

It is another object of the invention to provide compounds which areanti-pyretic agents.

It is a further object of the invention to provide a method forcontrolling inflammation in mammalian tissue.

It is a further object of the invention to provide a method forreleaving pain.

It is still another object of the invention to provide anti-inflammatorycompositions containing one or more N-alkylsulfonylbenzoylhaloa-lkylsulfonanilides as active ingredients therein.

It is still another object of the invention to provide anti-microbialcompositions containing one or more N- alkylsulfonylbenzoylhaloalkylsulfonanilides as active ingredients therein.

It is still another object of the invention to provide analgesiccompositions contaning one or more N-alkylsulfonylbenzoylhaloalkylsulfonanilides as active ingredients therein.

It is still another object of the invention to provide antipyreticcomposititons containing one or more N-alkylsulfonylbenzoylhaloalkylsulfonanilides as active ingredients therein.

Still other objects will be made apparent by the followingspecification.

DETAILED DESCRIPTION According to the present invention, there isprovided a class of compounds of the formula:

i R,SO2

RSO:

wherein R is alkyl or haloalkyl of one to four carbon atoms and R ischloromethyl or fiuoroalkyl of one to four carbon atoms, the fluoroalkylradical having at least one fluorine .atom bonded to the alpha carbonatom or at least two fluorine atoms bonded to a beta carbon atom, Y andY are the same or different and are selected from bydroxy, halogen,lower alkyl, lower haloalkyl, lower alkoxy and lower haloalkoxy, and nand n are the same or different and are zero to three.

chain perfluoroalkyl or partially fiuorinated alkyl, and it can containchlorine. When R is fluoroalkyl, it preferably has at least twofluorines bonded to the alpha carbon atom, or one fluorine bonded to thealpha carbon atom and at least two fiuorines bonded to the beta carbonatom. When n is zero, the ring adjacent to the alkylsulfonamido groupsis unsubstituted except for that group and the benzoyl group. Similarly,when n is zero, the second ring is unsubstituted except for the groupshown in the formula and attached thereto through the carbonyl link.

The compounds of the invention are generally active as anti-inflammatoryagents. The compounds in which R is fluoroalkyl containing one or twocarbon atoms are preferred, since such compounds are usually moreactive, and compounds wherein R is trifiuoromethyl or difluoromethyl aremost preferred. When R contains but one carbon atom, R is preferablyalkyl rather than haloalkyl.

Compounds of the invention wherein R is alkyl or haloalkyl of one or twocarbon atoms are preferred, because as the number of carbon atoms in Rincreases, anti-inflammatory activity decreases. When R is haloalkyl,halogen is fluorine or chlorine. Compounds wherein R is is methyl,ethyl, fiuoromethyl or chlororrrethyl are most preferred.

The radicals R and R may contain only fluorine or chlorine, or thesehalogens may both be present in one radical, or the two radicals maycontain diflerent halogens.

Compounds of the invention wherein the sulfonylsulfonamide group isoriented meta to the carbonyl of the benzophenone group are preferred.

The compounds of the present invention are prepared according to thefollowing reaction wherein R R, Y, Y, n and n are as definedhereinabove, M is a cation, eg of alkali metals, alkaline earth metals,amines or aluminum and X is halogen (preferably chlorine or fluorine, orthe residue of an anhydride grouping, i.e. OSO R). R and R may also bereversed in the foregoing equation.

Compounds wherein R contains one or two carbon atoms and is identicalwith R (i.e. both are haloalkyl) are optionally prepared by reacting atleast two equivalents of the appropriate haloalkylsulfonyl halide oranhydride with an aminobenzophenone of Formula IV, describedhereinafter.

A non-reactive organic solvent, preferably one in which the salts ofFormula II have some solubility, is used, such as 1,2-dimethoxyethane,diethyl ether, diisopropyl ether, acetone, chloroform, dichloromethaneand the like.

The reaction temperature may vary, from the freezing point to theboiling point of the solvent used, depending upon the reactivity of theintermediate compound of Formula II and the sulfonyl halide oranhydride. In some cases the reaction proceeds at the reflux temperatureof the solvent, while in others ice bath or room temperature issatisfactory.

The reaction product is generally isolated by filtration to remove thesalt MX which is formed as a byproduct, followed by evaporation of thesolvent. The product is dissolved in an organic solvent such aschloroform, dichloromethane, diethyl ether and the like and washed withwater and base to remove impurities such as unreacted starting materialand inorganic salts. The solution is dried, solvent removed in vacuo andthe residue is further purified, if necessary, by conventionaltechniques. Usually recrystallization from ethanol or ethanol-watermixtures is satisfactory.

The salts of Formula II are prepared from the corresponding acidformcompound msoildgl Y.: Y..' III by adding the stoichiometric amountof a base in inert solvent solution (aqueous or nonaqueous) to theacidic compound (III). The resulting solution is treated to remove thesolvent, e.g. by evaporation under reduced pressure to obtain the salt,usually as a dry powder. Appropriate bases for use in preparing themetal salts include -metal oxides, carbonates, bicarbonates andalkoxides.

Yn n' III uxsoiNn 0 wherein R 11, n, Y and Y are as previously definedand Q represents a halogen atom, preferably chlorine or fluorine, or thecorresponding anhydride grouping (R being defined as above).Approximately equivalent amounts of the reactants are brought togetherat temperatures most often ranging between about and 150 C. If necessaryor desirable, the reaction can be carried out in a pressure vessel. Thereaction is preferably, but not necessarily, carried out in the presenceof an acid acceptor such as the alkali or alkaline earth metalcarbonates and bicarbo'nates or a teritary amine such as pyridine,triethylamine or N,N-dimethylaniline. The amount of the acid acceptorcan be varied widely; however, a 10 mole percent excess of that amountof base sufficient to bind the liberated strong acid (HQ) is routinelyemployed.

The condensation is usually conducted in the presence of an appropriateinert organic solvent. Typical solvents suitable for this purpose aremethylene chloride, chloro- 4 form, carbon tetrachloride, benzene,toluene, bis(2-methoxyethyl) ether, N,N-dimethylformamide,1,2-dimethoxyethane and the like.

After reaction is complete, if the reaction solvent is not watermiscible, the production mixture can be extracted with a dilute aqueousbase solution. The product, in the form of a salt which is usuallysoluble in the aqueous layer, is precipitated therefrom by addition of amineral acid such as hydrochloric or sulfuric acid, and collected.Alternatively, the product mixture can be washed with aqueoushydrochloric acid, the solvent evaporated in vacuo, and the residuedissolved in a dilute aqueous base solution which is washed withdichloromethane and treated with decolorizing charcoal. The product, inthe form of a salt, is then isolated as described above.

If the reaction solvent is water miscible, the product is generallyobtained by dilution of the reaction mixture with water. The product, asolid or oil, is separated and purified by conventional methods. Thecompounds prepared according to the foregoing procedures are generallycrystalline solids purified, in general, by recrystallization fromaqueous alcohol, trichloroethylene, hexane, benzenehexane mixtures andthe like. Elution chromatography has also been found to be a usefulpurification technique.

Suitable haloalkanesulfonylanhydrides and halides (e.g. chlorides andfluorides) for use as starting materials in these procedures are knownto the art, for example:

fiuoromethanesulfonyl chloride, fiuorochloromethanesulfonyl chloride,difluoromethanesulfonyl chloride, chloromethanesulfonyl chloride,trifluoromethanesulfonic anhydride, 2,2,2-trifluoroethanesulfonylchloride, trifluoromethanesulfonyl chloride,

1, 1 ,2,2-tetrafiuoroethanesulfonyl chloride,2,2,3,3-tetrafluoropropanesulfonyl chloride,Z-hydroperfluoropropanesulfonyl chloride,

and many others disclosed, e.g., in U.S. Pat. 2,732,398.

Most of the aminobenzophenones, IV, are described in the generalchemical literature or can be prepared from corresponding knownsubstituted nitrobenzophenones by reduction. All of thenitrobenzophenones or aminobenzophenones not specifically disclosed inthe chemical literature are prepared by methods known in the literaturefor analogous compounds. Exemplary of such starting materials are:

S-amino-Z-chlorobenzophenone, 3-amino-4'-fluorobenzophenone,3-amino-5-bromobenzophenone, 3-amino-4'-ethylbenzophenone,

3 -amino-2'-ethoxybenzophenone, 3-amino-4'-ethoxybenzophenone, etc.

In some cases intermediates of Formula II are preferably prepared fromother intermediates of Formula II. For example,3-benzoyl-4-hydroxytrifluoromethanesulfonanilide may be prepared byreaction of 3-benzoyl-4methoxytrifluoromethanesulfonanilide withhydroiodic acid in acetic acid.

As noted previously, the compounds of the invention are as a classactive anti-inflammatory agents, although some are more active thanothers. The anti-inflammatory activity can be conveniently demonstratedusing assays designed to test the ability of these compounds toantagonize the local edema which is a characteristic of theantiinflammatory response (rat foot edema test) and to inhibit the onsetof the erythematous manifestation of inflammation (guinea pig erythernatest).

These are standard assays well known to those skilled in the art. Theyare described in journals and other publications. Leading references tothe rat foot edema test are:

(1) Adamkiewicz et al., Canad. J. Biochem. Physio, 33:

(2) Selye, Brit. Med. J. 2:1129, 1949; and (3) Winter, Proc. Soc. Exper.Biol. Med., 111:544, 1962.

Leading references to the guinea pig erythema test are:

( 1) Wilhelmi, Schweiz. Med. Wschr., 792577, 1949; and (2) Winder etal., Arch. Int. Pharmacodyn, 116:261,

Other standard assays well-known to those skilled in the art may also beused to detect anti-inflammatory activity in the compounds of thepresent invention, for example, the cotton pellet granuloma test or theadjuvant arthritis test.

Preferred compounds of the invention because of very highanti-inflammatory activity are:

N-methylsulfonyl-3 -benzoyltrifiuoromethanesulfonanilide,

N-fiuoromethylsulfonyl-3-benzoyltrifluoromethanesulfonanilide,

N-chloromethylsulfonyl-3 -benzoyltrifiuoromethanesulfonanilide, and

N-trifluoromethyl-3-benzoyltrifluoromethanesulfonanilide.

The compounds of the invention are preferably administered orally, forexample, as four percent acacia suspensions, but also may beadministered parenterally. Amounts are generally about 1 to 500 mg./kg.of body Weight of the mammal to be treated.

Many of the compounds of the invention are active as anti-microbialagents according to standard anti-microbial assays. Specifically, theanti-microbial activity of the compounds of the invention has beenevaluated using a variation of the original agar-plate diffusion methodof Vincent and Vincent (e.g., see Vincent, J. G., and Vincent, Helen W.,Proc. Soc. Exptl. Biol. Med., 55:162-164, 1944, and Davis, B. D., andMingioli, -E. S., Jour. Bact, 66:129-136, 1953).

The following examples are given for the purpose of further illustratingthe procedures of the present invention, but are not intended in any wayto be limiting on the scope thereof.

All melting points in the examples are uncorrected. 'Ihe boiling pointsand melting points are given in degrees centigrade and the pressures inmillimeters of mercury.

EXAMPLE 1 Intermediate compounds corresponding to Formula III areprepared according to the following general procedure:

In a three-necked round-bottomed flask equipped with a magnetic stirrer,a reflux condenser, a thermometer and an addition funnel are placed asubstituted aminobenzophenone (30 mmoles), chloroform (50 ml.) and N,N-dimethylaniline (33 mmoles). To this stirred mixture ahaloalkanesulfonic anhydride or haloalkanesulfonyl chloride (about 30mmoles) is added dropwise at such a rate that the reaction temperaturedoes not exceed 45 C. The mixture is then stirred two hours at ambienttemperature. The mixture is washed with five percent hydrochloric acid,then the solvent is removed in vacuo. The residue is taken up in fivepercent aqueous sodium hydroxide and washed with dichloromethane. Thebasic aqueous phase is then heated on a steam bath, treated withdecolorizing charcoal and acidified with concentrated hydrochloric acid.This mixture is then extracted with dichloromethane, and the extractsdried over magnesium sulfate. The solvent is removed in vacuo, and theproduct purified by recrystallization or (usually) column chromatographyfollowed by recrystallization, usually from saturated hydrocarbons ormixtures of benzene and saturated hydrocarbons.

Representative compounds prepared according to this procedure asintermediates are as follows.

Compound: Melting point, degrees 3-benzoyldifluoromethanesulfonanilide99-100.5 3-benzoylfluoromethanesulfonanilide 117-120 3-(4chloro-2-methylbenzoyl)trifluoromethanesulfonanilide 135-137 3-(4methylbenzoyl)fluoromethanesulfonanilide 118-120 3 (4chlorobenzoyl)difluorornethanesulfonanilide 127-129 3 benzoyl2,2,2-trifiuoroethanesulfonanilide 105.5-107 3-(4 methoxybenzoyl)difiuoromethanesulfonanilide 1 18-120 3 (4methoxybenzoyl)fiuoromethanesulfonanilide 116.5-118.5 4benzoyldifluoromethanesulfonanilide 124.5-126.53-benzoyltrifluoromethanesulfonanilide 99-1014-benzoyltrifluoromethanesulfonanilide 136-137 3-(4methylbenzoyl)trifluoromethanesulfonanilide 129.5-131.5 3 (4methoxybenzoyl)trifluoromethanesulfonanilide 1225-1245 3 (4chlorobenzoyl)trifluoromethanesulfonanilide 1235-1255 3 (3chlorobenzoyl)trifluoromethanesulfonanilide 101-102 3 (2chlorobenzoyl)trifiuoromethanesulfonanilide 72-74 3-(2methylbenzoyl)trifluoromethanesulfonanilide 92-933-benzoylperfluoroethanesulfonanilide 95-97 3 (4fluorobenzoyl)trifiuoromethanesulfonanilide l 3 4-13 6 3 benzoyl 4chlorotrifluoromethanesulfonanilide 106-108 3 benzoyl (2hydroperfluoroethane) sulfonanilide -80.5 3 benzoyl 4chlorodifluoromethanesulfonanilide 99-102 4-chloro-3-(4chlorobenzoyl)trifluoromethanesulfonanilide 82-83 4 chloro-3-(4fluorobenzoyl)trifluor methanesulfonanilide 133-134 3 (4fluorobenzoyl)difluoromethanesulfonanilide 80-843-benzoylchloromethanesulfonanilide -97 4 chloro-3-(4fluorobenzoyl)difluoromethanesulfonanilide 101-103 4 chloro-3-(4chlorobenzoyl)tiifluoromethanesulfonanilide 81-83 3 (3trifluoromethylbenzoyl)trifluoromethanesulfonanilide 86-883-benzoylperfluoro n butanesulfonanilide, B.P. 186 C./0.09 mm.

The following intermediate compounds are prepared by hydroiodicacid-acetic acid cleavage of the corresponding methoxy derivatives:

3-benzoyl-4-hydroxytrifluoromethanesulfonanilide,

M.P. 133-136, and 3- Z-hydroxybenzoyltrifluoromethanesulfonanilideEXAMPLE 2 The following is exemplary of the preparation of the salts ofFormula II.

To a solution of 12.21 g. of reagent grade sodium hydroxide (0.305 mole)in 300 ml. of water are added 95 g. of3-benzoyldifiuoromethanesulfonanilide (0.305 mole). The mixture isstirred until dissolution is complete and the solution has a pH of 7.2(sensitive pH paper).

Water is removed to give a yellow solid which is taken up in about 200ml. of glyme and treated with activated charcoal. The clear solution isthen added dropwise with vigorous stirring to liters of ethyl ether. Thecrystalline salt is isolated by filtration, washed with 4 liters ofethyl ether and dried to give the pure product, M.P. (dec.) 235 C.

Analysis.-Calculated for C H F NaNO S (percent): C, 50.45; H, 3.05.Found (percent): C, 50.6; H, 3.2.

The following salts are prepared using the general method of Example 2:

potassium 3-benzoyltrifluoromethanesulfonanilide lithium3-benzoyltrifluoromethanesulfonanilide dimethyl-Z-hydroxyethylammonium3-benzoyltrifiuoromethanesulfonanilide triethylammonium3-benzoyltrifluoromethanesulfonanilide chlorine salt of3-benzoyltrifluoromethanesulfonanilide.

EXAMPLE 3 The compounds of the invention (Formula I) are preparedaccording to the following general procedure: In a three-neckedround-bottom flask equipped with a magnetic stirrer, a reflux condenserand an addition funnel is placed a salt of ahaloalkylsulfonamidobenzophenone of Formula II (30 millimoles) inacetone (200 ml.) or other suitable solvent. To this stirred mixture isadded a compound of the formula RS0 X, wherein R and X are as previouslydefined (about 30 millimoles). The mixture is stirred at roomtemperature for at least one hour, although longer reaction times andhigher temperatures may increase yields or initiate sluggish reactions.The solution is filtered then the solvent is removed in vacuo, and theresidue is dissolved in dichloromethane or other suitablewater-immiscible organic solvents, then washed with water and base. Theproduct is recovered by evaporation of the solvent and recrystallized,sublimed, distilled or chromatographed if further purification isdesired.

Representative compounds prepared according to this procedure are listedbelow:

Compound: Melting point, degrees 'N-fluoromethylsulfonyl 3benzoyltrifluoromethanesulfonanilide 1 985-1005 N-methylsulfonyl 3benzoyltrifiuoromethanesulfonanilide 1081 Ntrifluoromethylsulfonyl-3-'benzoyltrifluoromethanesulfonlanilide68.570.5 N-chloromethylsulfonyl 3 benzoyltrifluoromethanesulfonanilide l10-l 12 N n butylsulfonyl 3 benzoyltrifluoromethanesulfonanilide 81-84Analysts.-CaIculated for cmHllFiNo sg (percent): C, 42.3 'H, 2.6; N,3.3. Found (percent) C, 42.6 H, 2.7; N, 3.3.

Additional compounds of the invention prepared by the preceding methodsare as follows:

N-methylsulfonyl-3 -benzoyldifiuoromethanesulfonanilideN-methylsulfonyl-3 -b enzoylfiuoromethanesulfonanilideN-fluoromethylsulfonyl-S 4ch1oro-2-methylbenzoyl)trifluoromethanesulfonanilide N-methylsulfonyl-3 (4-methylbenzoyl)fluoromethanesulfonanilide N-methylsulfonyl-3- (4-chlorobenzoyldifiuoromethane'sulfonanilide N-methylsulfonyl-3-benzoyl2,2,Z-trifluoromethanesulfonanilideN-methylsulfonyl-3- 4-me thoxybenzoyl) difiuorometh anesulfonanilideN-methylsulfonyl-3 (4-methoxybenzo yl) fluoromethanesulfonanilideN-methylsulfonyl-4-benzoyldifluoromethanesulfonanilideN-chloromethylsulfonyll-b enzoyltrifluoromethanesulfonanilideN-fluoromethylsulfonyl-3- (4-methylbenzoyl) trifluoromethanesulfonanilide N-fluoromethylsulfonyl-3 (4-methoxyb enzoyl) trifluoromethanesulfonanilide N -fiuorom ethylsulfonyl-3 4-chlorobenzoyl)trifluoromethane sulfonanilide N-fluoromethylsulfonyl-3 (3-chlorobenzoyl trifluoromethanesulfonanilide N-fluoromethylsulfony1-3(Z-methylb enzoyl) trifluoromethane'sulfonanilideN-fiuoromethylsulfonyl-3-benzoylperfluoromethanesulfonanilideN-fluoromethylsulfonyl-3- (4-fluorobenzoyl) trifluoromethanesulfonanilide N-fluoromethylsulfonyl-3 -benzoyl-4-chlorotrifiuoromethanesulfon anilide N-fluoromethylsulfonyl-3-b enzoyl-(Z-hydroperfluoroethane) sulfonanilideN-methylsulfonyl-3-benzoyl-4-chlorodiflu0romethanesulfonanilideN-methylsulfonyl-4-chloro-3 4-chlorob enzoyl)trifluoromethanesulfonanilide N-methylsulfonyl-4-chloro-3-(4-fiuorobenzoyl) trifluoromethanesulfonanilide N-methylsulfonyl-3-4-fluorobenzoyl) difiuoromethanesulfonanilideN-methylsulfonyl-3-benzoylchloromethanesulfonanilideN-ethylsulfonyl-4-chloro-3 (4-fluorobenzoyl)difluoromethane'sulfonanilide N-methylsulfonyl-4-chloro-3(4-chlorobenzoyl difiuoromethanesulfonanilide N-methylsulfonyl-3-3-trifiuoromethylbenzoyl) trifluoromethanesulfonanilideN-methylsulfonyl-3 -benzoylperfluoro-n-butanesulfonanilide What isclaimed is: 1. A comp ound of the formula n Y'n' wherein R is alkyl orhaloalkyl of one to four carbon atoms and R is chloromethyl,fluoroalkyl, or chlorofluoroalkyl wherein the alkyl groups have one tofour carbon atoms, the fluoroalkyl or chlorofiuoroalkyl radicals havingat least one fluorine atom bonded to the alpha carbon atom or at leasttwo fluorine atoms bonded to a meta carbon atom, Y and Y are the same ordifferent and are selected from hydroxy, halogen, lower alkyl, lowerhaloalkyl, lower alkoxy and lower haloalkoxy, and n and n are the sameor different and are zero to three.

2. A compound according to claim 1 wherein n and n are zero.

3. A compound according to claim 1 wherein R is trifiuoromethyl.

4. A compound according to claim 1 wherein the nitrogen atom and thecarbonyl group of the formula are oriented meta to one another.

5. A compound according to claim 4 wherein R and R each contain only onecarbon atom.

6. N-methylsulfonyl-3 benzoyltrifluoromethanesulfonanilide according toclaim 1.

7. N fluoromethylsulfonyl-3-benzoyltrifluoromethanesulfonanilideaccording to claim 1.

8. N-trifiuoromethylsulfonyl 3 benzoyltrifluoromethanesulfonanilideaccording to claim 1.

9. N-n-butylsulfonyl 3-benzoyltrifluoromethanesulfonanilide according toclaim 1.

RSO

9 10 10. N-ch1oromethy1su1fonyl-3-benzoyltrifluoromethane- ReferencesCited 8111f anilide according t0 claim 1. UNITED STATES PATENTS th ulIYDA e form a 3,576,866 4/1971 Robertson et a1. 260-556 F 0 5 II-IENRYR. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner RSOz US.Cl. X.R.

wherein R is methyl or halomethyl and R is chloromethyi 10 260 556 SN556 A 570 A 543 424 321 or a fluoromethyl containing at least onefluorine atom.

UNITED STATES PATENT OEEIEE CERTIFICATE 0F CORQTEQN Patent No. 3,661,990Dated May 9,1972

Inventor-(s) Joseph Kenneth? Harrington It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

Column 1, line 43, "containing" should be "containing- Column 2, line28, "R- is is methyl," should be --R is methyl," Column 2, line ,5, I II should be inserted under the formula Column 3, line 68, 'terioary"should be -tertia.ry

Column 4, line 5, "produc cion" should be -product-'-- Column 7, line25, "In" should be "Into-- Column 7, line 70, "trifluoromethane" shouldbe --trifluoroethane- Column 8, line 15, "benzoylperfluoromethane-"should be -benzoylperfluoroethane- Column 8, line 5M, "meta" should be--beta-- Signed and sealed this 1st day of May 1973.

(SEAL) Attest:

EDWARD M. FLETCHER, JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents FORM FO-IOSO (10-69) USCOMM-DC 60376-P69 s u.s, GOVERNMENTPRINTING OFFICE: I969 0-366-336

